Cardiovascular diseases account for nearly 85 percent of deaths in patients with type 2 diabetes mellitus. Studies indicate that the risk for atherosclerotic cardiovascular disease is two to four times higher in patients with type 2 diabetes. While presence of cardiovascular disease can be detected, there are no widely accepted biomarkers for screening and identifying individuals at risk for early vascular disease in patients with type 2 diabetes. My work is targeted on circulating monocytes which play an important role in atherogenic vascular disease as well as diabetes. We speculate that there could exist a subset of monocytes which may play a distinct role in promoting atherosclerosis in patients with type 2 diabetes.We propose to identify these varying subsets of monocytes, and find factors which could serve as individual markers or define a characteristic profile. We are also interested in analysing the response of monocytes to atherogenic lipids as well as hyperglycaemia in vitro, which may provide clues to their in vivo response in patients with type 2 diabetes mellitus.

Varicose veins are the most frequent outcome of chronic venous insufficiency. Haemorrhage, thrombophlebitis, oedema, skin pigmentation, eczema, lipodermatosclerosis and venous ulceration are complications of venous hypertension due to varicosities. The exact primary abnormality and pathogenesis of the disease remains unexplored. The role of familial incidence in primary varicose vein is well accepted. Non-genetic factors such as age, gender, pregnancy, obesity, prolonged standing also play important modulating roles, complicating the task of disease analysis. My aim is to identify genetic and molecular markers for early detection of individuals susceptible for varicose veins. Reverse genetic techniques along with differential expression studies of tissue samples will be used to identify new candidate genes. Whole genome-wide scanning will be performed to analyze the genetic markers prevailing in varicose families so as to identify other risk-conferring genes. Secreted proteins from varicose venous endothelium will also be evaluated in terms of their role as markers for early onset of venous insufficiency. My studies are expected to delineate the pathogenetic mechanisms of varicose veins.

Vascular inflammation is a key process in the initiation and progression of atherosclerotic vascular lesions. Inflammatory processes are also implicated in the destabilization of established atherosclerotic plaques. Recently discovered class of RNAs called microRNAs (miRNAs) have been shown to directly control vascular inflammation. However, the role of miRNAs in the pathogenesis of the atherosclerosis is yet to be completely delineated. We propose to elucidate regulatory effects of miRNAs on pathways that control the development of atherosclerotic vascular lesions. We speculate that expression of inflammatory genes involved in atherogenesis is regulated by different miRNAs. One of the initial critical events in the pathogenesis of atherosclerosis is the diapedesis of circulating monocytes into the arterial intima and this step is regulated by a CC chemokine namely monocyte chemoattractant protein-1 (MCP-1). We hypothesize that the expression of MCP-1 in the aortic tissue is regulated by specific miRNAs and modulating these miRNAs may help to attenuate the initiation and progression of atherosclerosis.

Heart failure is a condition in which cardiac output becomes insufficient to meet the body’s needs and it invariably worsens with time. It is well recognised that during the evolution of heart failure, remodelling of the heart occurs at genomic, cellular and tissue levels. Cardiovascular ‘remodeling’ activities are adaptive mechanisms to normalise the pump function, but continuous remodeling leads to ventricular dilatation, hypertrophy and contractile dysfunction. Paracrine and autocrine interactions involving cardiac endothelial cells and cardiac myocytes could significantly modulate remodeling events in a diseased heart. However, only a few studies have been done in this domain. Endocardial endothelial dysfunction is seen similarly as coronary micro-vascular endothelial (MVE) dysfunction in the failing heart, but less is known about to what extent endocardial endothelial cells (EEC) control myocardial remodeling in the adult heart. I propose to analyze the changes that occur in the cardiac endothelial cells during evolution of cardiac hypertrophy in pressure overload and during decompensation resulting in cardiac failure. Further, attempts would be made to find whether EEC dysfunction critical to adverse myocardial and vascular remodelling could be modulated through pharmacologic agents.

One of the hall mark features of adult stem cells is their relative quiescence. In heart, adult stem cells are maintained in a quiescent state and are triggered by the stimulation of growth factors/ inflammatory molecules during pathological challenge. Defining the cell cycle regulation in adult cardiac stem cells may unravel the key regulators of cardiac lineage self- renewal and differentiation during development and disease. I am interested in understanding the mechanisms involved in regulation of the cell cycle in adult cardiac stem cells and in elucidating the signalling pathways involved in the self renewal and differentiation of cardiac stem cells.

Congenital heart disease refers to abnormalities in the heart’s structure or function that arise before birth. Congenital heart diseases are the leading non- infectious cause of death in children in their first year of life. Tetralogy of Fallot (ToF) is a very common cyanotic congenital malformation and accounts for 10% of all congenital heart diseases. The exact cause of the disease is unknown. Multiple factors are suggested. There is a 15% prevalence of 22q11 deletion in the chromosomes of patients with Tetralogy of Fallot. When 22q11 deletion is not present, the reason for the origin of disease is unknown. My area of interest is the development of right ventricle and its out flow tract which may be disturbed in ToF. I propose to investigate through mutational analysis whether there is any link between cardiac lesions in Tetralogy of Fallot and the genes involved in the development of the right ventricular outflow tract. My study promises to yield insights for better understanding of the pathogenesis of the disease.

In patients with left heart failure, elevation in left ventricular filling pressure results in reactive increase in pulmonary vascular resistance leading to pulmonary hypertension (PH). This secondary PH may reflect remodeling of pulmonary vascular wall resulting in vascular stiffness and reduced vasodilator responsiveness. About two thirds of patients with left ventricular (LV) failure have associated PH. The mortality in patients with LV failure with PH is two fold higher compared to mortality in patients with LV failure without PH. Considerable evidence indicates that impairment of endothelial function is a major cause of pulmonary vascular remodeling in heart failure. I propose to study the nature of endothelial dysfunction in PH in LV failure and the molecular mechanism of microvascular remodeling in LV failure associated PH. Better understanding of molecular mechanisms may help in identifying strategies for reversal of pulmonary vasculature remodelling in progressive LV failure.

Email: binilraj@rgcb.res.in